Production process of optically pure 2-(4- hydroxyphenoxy)-propionic acid compounds

ABSTRACT

A process for producing optically pure R-hydroxyphenoxypropanoic acid or a salt or ester thereof by reaction of hydroquinone or a salt thereof with an S-halopropanoic acid or a salt thereof in the presence of a mild reducing agent.

This application is a 371 of International Application No.PCT/GB2004/003497 filed Aug. 16, 2004, which claims priority to GB0322917.6 filed Sep. 30, 2003, the contents of which are incorporatedherein by reference.

The present invention relates to a process for the production ofoptically pure R-hydroxyphenoxypropanoic acid or a salt or ester thereofand its use in making herbicidal products on an industrial scale.

Optically pure R-2-(4-hydroxyphenoxy)propanoic acid (3) can be preparedby the reaction of hydroquinone (2) with an S-2-halopropanoic acid (1)where X is chloro or bromo and is preferably chloro, in the presence ofa base.

The problems associated with producing optically pureR-2-(4-hydroxyphenoxy)propanoic acid from hydroquinone and anS-2-halopropanoic acid are discussed and the relevant prior art isreviewed in EP352168. In particular, over-alkylation of hydroquinone togive the bis-acid (4) and oxidation of hydroquinone to give highlycoloured by-products are two serious problems. The solution offered inEP352168 is to perform a complex purification procedure.

On an industrial scale it is desirable to have a simple method for thepreparation of R-2-(4-hydroxyphenoxy)propanoic that is essentially freeof products of over-alkylation, that is not contaminated by highlycoloured by-products and therefore does not require any complex orexpensive purification procedures. The applicants have surprisinglyfound that the use of a mild reducing agent in the manufacture ofR-2-(4-hydroxyphenoxy)propanoic acid enables a product to be isolatedthat meets the above criteria.

There is therefore provided a process for producingR-2-(4-hydroxyphenoxy)propanoic acid by reaction of hydroquinone or asalt thereof with an S-2-halopropanoic acid or a salt thereof, in thepresence of a mild reducing agent.

The S-2-halopropanoic acid is S-2-bromopropanoic acid orS-2-chloropropanoic acid, preferably S-2-chloropropanoic acid.

In one preferred embodiment excess hydroquinone is recovered forrecycle.

It is preferred that isolation of the R-2-(4-hydroxyphenoxy)propanoicacid produced by the reaction is carried out by acidification forexample with a mineral acid, especially hydrochloric acid, andfiltration.

If necessary or desired the R-2-(4-hydroxyphenoxy)propanoic acid may beconverted to a salt or ester thereof by conventional techniques.

The preferred solvents for the reaction are water or water misciblesolvents such as methanol or ethanol, alone or in admixture with water.

Preferred bases are alkali metal hydroxides especially sodium hydroxide.

Preferably the reaction is carried out at a temperature of 10-100° C.,more preferably 30-70° C.

The reaction may be carried out at atmospheric pressure or up to 1 barof excess pressure.

It is advantageous to use a deficiency of the S-2-halopropanoic acid, asits salt, in the reaction with hydroquinone, typically 0.25-0.75 mol/moland preferably 0.3-0.6 mol/mol. Preferred salts are alkali metal salts,more preferably the sodium salt.

Suitably an excess of a stoichiometric amount of base on thehydroquinone is used. Preferably the base is used at between 1.5 and 2.5mol/mol on hydroquinone and more preferably at 1.6-2.0 mol/mol.

The mild reducing agent is preferably present throughout the process. Itmay be added to the process as a solid or as a solution. Incrementaladditions may be made during the process.

Suitably the mild reducing agent is a neutral or a charged low oxidationstate sulphur species, such as sulphur dioxide, a sulphite, abisulphite, a hydrosulphite, a metabisulphite, a sulphenic acid, asulphinic acid, for example formamidine sulphinic acid, or a lowoxidation state phosphorous species such as a phosphite orhypophosphite, or hydrazine, a hydrazine derivative, or ascorbic acid.

Preferred mild reducing agents are alkali metal sulphite or bisulphitesalts such as sodium sulphite, sodium bisulphite, potassium sulphite orpotassium bisulphite.

A preferred mild reducing agent is sodium bisulphite.

The amount of the mild reducing agent used is between 0.01% and 10% byweight on the amount of hydroquinone and is preferably between 0.1% and5% and most preferably between 0.5% and 2%.

The process is preferably conducted essentially in the absence of oxygenby use of an inert gas blanket, for example nitrogen.

If desired the process can be adopted for the production ofS-2-(4-hydroxyphenoxy)propanoic acid by substituting anR-2-halopropanoic acid for the S-2-halopropanoic acid as a startingmaterial.

R-2-(4-hydroxyphenoxy)propanoic acid is used in the manufacture ofseveral commercial herbicides such as quizalofop-P-ethyl,haloxyfop-P-methyl, fluazifop-P-butyl, clodinafop, cyhalofop-butyl andfenoxaprop-P-ethyl.

Therefore, in another aspect of the invention there is provided aprocess for the manufacture of quizalofop-P-ethyl, haloxyfop-P-methyl,fluazifop-P-butyl, clodinafop, cyhalofop-butyl or fenoxaprop-P-ethyl bya) producing R-2-(4-hydroxyphenoxy)propanoic acid by reaction ofhydroquinone or a salt thereof with a S-2-halopropanoic acid or a saltthereof, in the presence of a mild reducing agent, b) reacting theR-2-(4-hydroxyphenoxy)propanoic acid with the appropriate halo-aryl orhalo-heteroaryl moiety to give a R-2-((4-aryloxy orheteroaryloxy)phenoxy)propanoic acid and c) esterification of the acidfrom step b) to give quizalofop-P-ethyl, haloxyfop-P-methyl,fluazifop-P-butyl, clodinafop, cyhalofop-butyl or fenoxaprop-P-ethyl.

The appropriate halo-aryl or halo-heteroaryl moieties are2-halo-6-chloro-quinoxaline for quizalofop-P-ethyl;2-halo-3-chloro-5-trifluoromethylpyridine for haloxyfop-P-methyl;2-halo-5-trifluoromethylpyridine for fluazifop-P-butyl;2-halo-5-chloro-3-fluoropyridine for clodinafop;4-halo-3-fluorobenzonitrile for cyhalofop-butyl and2-halo-6-chloro-benzoxazole for fenoxaprop-P-ethyl where halo is chloroor bromo.

The conversion of R-2-(4-hydroxyphenoxy)propanoic acid to the acids ofstep b) and and esters of step c) is well known to the skilled persone.g. in Advanced Organic Chemistry, Jerry March, John Wiley & Sons,1992, p 393.

The invention will now be further illustrated with reference to thefollowing Example.

-   The product quality was determined by HPLC and the colour was    determined as follows. About 10 gm of    R-2-(4-hydroxyphenoxy)propanoic acid was suspended in 10 mls water    and adjusted to pH 7 with potassium hydroxide solution before being    made up to 10 mls with more water. The absorbances of the solution    were measured at 420 and 650 nm and are expressed as extinctions    coefficients (ε, absorbance for a 1 molar solution and a 1 cm path    length.).

EXAMPLE 1 Preparation of R-2-(4-hydroxyphenoxy)propanoic acid in thepresence of sodium bisulphite with recycling of hydroquinone

Step 1

-   Hydroquinone (574 g, 5.22 mol) was charged to a reaction flask    followed by sodium bisulphite (5.74 g) and water (1014 g) and a    nitrogen blanket was established. The mixture was stirred and heated    to 50° C. and 47% solution of sodium hydroxide (799.5 g, 9.39 mol)    was added. The solution was heated to 65° C. and an aqueous solution    of S-2-chloropropanoic acid sodium salt (544.4 g, 32.5% as the free    acid, 1.63 mol) was added. The reaction mixture was held at 65° C.    for 4 hours. After this period, the total reaction mass weighed    2937.6 g and had a R-2-(4-hydroxyphenoxy)propanoic acid content of    8.60%, equivalent to 252.54 product or 85% yield. 700 g of water    were added and the temperature adjusted to below 45° C. Phosphoric    acid (120 g) was added to adjust the pH to about 11 and then 98%    sulphuric acid (250 g) was added to reduce the pH to 6.5-7.5, the    temperature being controlled at 55° C. during these additions. The    solution was then extracted with four successive 638 ml portions of    methylisobutylketone (MiBK) to give a solution of hydroquinone in    MiBK for use in the next cycle.    Step 2.-   The MiBK extracts of hydroquinone were then extracted with a    solution of sodium hydroxide (687 g 47% solution), sodium bisulphite    (4.02 g) and water (1013 g) whilst maintaining an inert atmosphere    (nitrogen). The aqueous extract of hydroquinone was charged to a    reaction flask followed by fresh hydroquinone (172.2 g), 47% sodium    hydroxide solution (111.9 g) and sodium bisulphite (1.72 g), all    under a nitrogen blanket. The solution was heated to 65° C. and an    aqueous solution of S-2-chloropropanoic acid sodium salt (544.4 g,    32.5% as the free acid, 1.63 mol) was added at this temperature. The    reaction mixture was held at 65° C. for 4 hours. 700 g of water were    added and the temperature adjusted to below 45° C. Phosphoric acid    (120 g) was added to adjust the pH to about 11 and then 98%    sulphuric acid (250 g) was added to reduce the pH to 6.5-7.5, the    temperature being controlled at 55° C. during these additions.-   The un-reacted hydroquinone was removed by extraction with MiBK as    above and the residual aqueous phase was then adjusted to pH 2±0.2    using 98% sulphuric acid and extracted with two 250 ml portions of    MiBK to extract the R-2-(4-hydroxyphenoxy)propanoic acid. The two    extracts were combined and washed with a solution of potassium    hydroxide (155.5 g of 85% strength material) and sodium bisulphite    (2.15 g) in water (280 g).

The aqueous solution of R-2-(4-hydroxyphenoxy)propanoic acid potassiumsalt was acidified to pH 1 with 32% hydrochloric acid and thetemperature adjusted to 20° C. The slurry was then filtered and thesolid product washed with water (one wash 260 g and then two washes at230 g). After washing, the product was dried before weighing andanalysis.

-   Weight 188 g-   Strength 99.4%-   Bis acid 0.3%-   Yield 63%-   Colour Absorbance at 650 nm, 0.023, at 420 nm, 0.197-   The table below gives absorbance data for product obtained by the    process of the invention and the same process but without the use of    sodium bisulphate.

Reaction Observed color ε at 650 nm ε at 420 nm Control without anyLight brown 0.153 1.614 sodium bisulphite Addition of 5% sodium White0.061 0.243 bisulphite on hydroquinone

1. A process for producing R-2-(4-hydroxyphenoxy)propanoic acid or asalt thereof by reaction of hydroquinone or a salt thereof with aS-2-halopropanoic acid or a salt thereof in the presence of a mildreducing agent.
 2. A process according to claim 1 wherein theS-2-halopropanoic acid is S-2-chloropropanoic acid.
 3. A processaccording to claim 1 wherein the excess hydroquinone is recovered forrecycle.
 4. A process according to claim 1 wherein the mild reducingagent is a neutral or a charged low oxidation state sulphur species, alow oxidation state phosphorous species, hydrazine, a hydrazinederivative or ascorbic acid.
 5. A process according to claim 4 whereinthe mild reducing agent is sulphur dioxide, a sulphite, a bisulphite, ahydrosulphite, a metabisulphite, a sulphenic acid, a sulphinic acid, aphosphite, hypophosphite, hydrazine, a hydrazine derivative or ascorbicacid.
 6. A process according to claim 5 wherein the mild reducing agentis an alkali metal sulphite or bisulphite.
 7. A process for themanufacture of quizalofop-P-ethyl, haloxyfop-P-methyl,fluazifop-P-butyl, clodinafop, cyhalofop-butyl or fenoxaprop-P-ethyl by:a) producing R-2-(4-hydroxyphenoxy)propanoic acid by reaction ofhydroquinone or a salt thereof with S-2-halopropanoic acid or a saltthereof, in the presence of a mild reducing agent, b) reacting theR-2-(4-hydroxyphenoxy)propanoic acid with the appropriate halo-aryl orhalo-heteroaryl moiety to give a R-2-((4-aryloxy orheteroaryloxy)phenoxy)propanoic acid and c) esterification of the acidfrom step b) to give quizalofop-P-ethyl, haloxyfop-P-methyl,fluazifop-P-butyl, clodinafop, cyhalofop-butyl or fenoxaprop-P-ethyl. 8.A process according to claim 5 wherein the sulphinic acid is formamidinesulphinic acid.